Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.
Examples of kinases in the protein kinase family include, without limitation, Abl1 (v-Abl Abelson murine leukemia viral oncogene homolog 1), Akt, Alk, Bcr-Abl1, Blk, Brk, Btk, c-Kit, c-Met, c-Src, c-Fms, CDK1-10, b-Raf, c-Raf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Flt-1, Fps, Frk, Jak, KDR, MEK, PDGFR, PIK, PKC, PYK2, Ros, Tie, Tie2, and Zap70. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.
Bruton's tyrosine kinase (Btk) plays a key role in promoting B cell proliferation and survival through participation in the B cell receptor (BCR) signaling pathway and represents a promising new drug target. Targeted therapies that suppress BCR signaling have emerged as promising agents in the treatment of several B cell malignancies. To this end, attempts have been made to identify small molecules which act as Btk inhibitors. For example, U.S. Pat. No. 7,982,036 describes 4,6-disubstituted pyrimidine compounds as useful kinase inhibitors targeting the Tec kinase family. The disclosed compounds include Btk inhibitors. Another class of Btk inhibitors has been disclosed in U.S. Pat. No. 8,088,781.
Thus, the compounds that can inhibit protein kinases such as Bruton's tyrosine kinase (Btk) activity are highly desired.